Effects of manganese oxide on monkeys as revealed by a combined neurochemical, histological and neurophysiological evaluation.

Four monkeys were exposed to a total of 8 g each of manganese as oxide by repetitive subcutaneous injections during 5 months, after which they were left for 1 week to 6 months before they were sacrificed. All animals developed hyperactive behaviour after about 2 months. About 5 months after the start of the exposure the animals became hypoactive with an unsteady gait, and subsequently an action tremor appeared in some of the animals. The animals lost power in both upper and lower limbs and the movements of the hands and feet were very clumsy. The serum content of manganese rose 10-40 times during the exposure time and the content in brain was generally increased more than 10 times, with the highest content found in globus pallidus and putamen. The observed neurochemical effects were also largest in globus pallidus and putamen. In these regions there was a considerable depletion of dopamine and 3,4-dihydroxyphenylacetic acid, while the homovanillic acid content remained almost unchanged. A severe neuronal cell loss was observed in globus pallidus but not in other regions. This is in accordance with results from the most recent neuropathological study of a human suffering from chronic manganese poisoning [Yamada et al. (1986) Acta Neuropathol 70: 273-278] where globus pallidus was devoid of neuronal cells while the content of pigmented cells in substantia nigra was normal. Our data suggest a reduction in number of dopaminergic nerve terminals, as the activity of the dopamine synthesizing enzyme DOPA-decarboxylase was also lowered.(ABSTRACT TRUNCATED AT 250 WORDS)

Trace elements in the human central nervous system studied with neutron activation analysis.

The central nervous system (CNS) should be especially sensitive to disturbances in trace element concentrations because of its high metabolic rate and low capacity for regeneration. Comparatively few studies have been made on trace elements in the CNS, which prompted us to begin a study of trace elements in four different brain lobes of the CNS, as well as in the spinal cord. Samples were obtained at autopsy and handled carefully in order to avoid contamination. They were freeze-dried and sealed in quartz tubes that were irradiated in a nuclear reactor. A simple chemical separation into six fractions was performed. The gamma spectra for these fractions was registered using a Ge(Li) detector and a computerized multichannel analyzer. Results for the following elements were obtained: Ca, Cd, Co, Cr, Cs, Cu, Fe, Rb, Se, and Zn, as well as for Na and K (not reported). Other elements were also detected in some samples. Using this technique, brain samples from ten patients with Alzheimer's disease and ten control cases were examined.

Effects of manganese chloride on the rat developing nervous system.

Sprague-Dawley rats were exposed to sublethal doses of manganese chloride during their postnatal development period up to 44 days of age. They showed transient clinical signs of disease and a decreased homovanillic acid (HVA) content in the striatum and hypothalamus between 15 and 22 days of age. The manganese content in the brain was increased 20-40 times during this period as determined with neutron activation analyses. In spite of this no structural damage or signs of maturation disturbances in the nervous system were found. Interruption of manganese exposure reversed the changes in HVA content.

Selenium supplementation in X-linked muscular dystrophy. Effects on erythrocyte and serum selenium and on erythrocyte glutathione peroxidase activity.

The selenium concentrations in serum and erythrocytes and the erythrocyte glutathione peroxidase activity were determined in 15 boys with the Duchenne type and in 5 boys with the Becker type of X-linked muscular dystrophy before and during long-term selenium and alpha-tocopherol supplementation and compared with values in unsupplemented controls. The purpose of the treatment was to improve the muscular strength. Twelve of the 20 patients had pretreatment levels of selenium in serum that were within the 95% confidence limit of the unsupplemented control children. The values in 2 patients, both with the Duchenne type of muscular dystrophy, fell below this level. Selenium supplementation in a daily dose of 6 micrograms/kg/day for 6 months caused a substantial rise in both serum and erythrocyte selenium, suggesting suboptimal pretreatment body contents of selenium. The greatest increases in both serum and erythrocyte selenium were observed in subjects with initially low selenium levels. Only in 4 of the 20 patients did the selenium supplementation result in a significant rise in erythrocyte glutathione peroxidase activity. As no sure improvement was noted in muscular strength during this treatment period, the Se dose was increased to 20 micrograms/kg/day. This resulted in a further rise in both serum and erythrocyte selenium, but not in erythrocyte glutathione peroxidase activity.

Selenium in plasma and erythrocytes in patients with Down's syndrome and healthy controls. Variation in relation to age, sex and glutathione peroxidase activity in erythrocytes.

The mean plasma selenium concentration (P-Se) in 65 patients with Down's syndrome (DS) did not differ from that in 90 healthy controls. The concentration of selenium in the erythrocytes (E-Se) was higher in DS patients than in controls (p less than 0.001). P-Se and E-Se increased progressively with age through childhood in both DS children and controls. The former children, however, started out with higher levels of E-Se and reached adult concentrations earlier (at 7-17 years) than controls (greater than or equal to 18 years). Adult DS patients and controls did not differ in their mean P-Se or E-Se concentration. There was a significant correlation between P-Se and E-Se both in DS patients and in controls. In DS patients each of these two variables was significantly correlated to glutathione peroxidase (GSH-Px) activity in erythrocytes. A sex difference in the DS children, but not in the controls, was observed with regard to P-Se and E-Se levels, these being higher in DS girls during childhood (0-17 years). This was in accordance with an earlier finding of higher GSH-Px activity in DS girls than in DS boys.

Concentration of selenium in plasma and erythrocytes during total parenteral nutrition in Crohn's disease.

Plasma- and erythrocyte-selenium concentrations were determined in five consecutive patients with Crohn's disease given preoperative total parenteral nutrition - nil per os - for a mean period of 34 days per patient. No blood components were administered during the total parenteral nutrition. Before the total parenteral nutrition the plasma-selenium level and, to a less extent, the erythrocyte-selenium levels were below the reference values. After three weeks of total parenteral nutrition both concentrations had fallen. There were, however, clinical and biochemical signs of improvement during the total parenteral nutrition, as indicated by an increase in body weight, P-albumin and P-transferrin. In one female patient given 39 days of preoperative total parenteral nutrition containing 0.06 mumol (5 micrograms) selenium per 24 h the decreasing levels of plasma-selenium and erythrocyte-selenium were both correlated to the duration of the total parenteral nutrition (r = 0.87 and 0.96, respectively). The results suggest that total parenteral nutrition patients may be at risk for selenium deficiency, and that a supplementary administration of selenium via total parenteral nutrition may be required.

Urinary excretion and blood concentrations of trace elements and electrolytes during total parenteral nutrition in Crohn's disease.

Urinary excretion of trace elements (Cr, Co, Cu, Fe, Mn, Se, Zn, Sb, Cs, Rb), electrolytes (Na, K, Ca, Mg, phosphate), and nitrogen were determined during days 1-5 and 54-79 of total parenteral nutrition (TPN, nil per os) given to six patients with Crohn's disease. Whole-blood concentrations of Cr, Fe, Zn, Cs, and Rb and serum concentrations of electrolytes were determined before the TPN and on days 54-79 of TPN. The 24-hr urinary excretion of zinc was lower on days 54-79 than on days 1-5, but the rates of excretion of the other essential trace elements during TPN displayed no significant change. The urinary excretion of Cu, Fe, and Mn was numerically lower than the intravenous administration of these elements during days 1-5 and 54-79 of TPN, whereas the urinary excretion of zinc was lower than the supply only during days 54-79. The whole-blood concentration of zinc was low but constant during TPN, whereas the initially low levels of Cr and Fe were normalized on days 54-79. The results suggest that the supply of the essential trace elements Cr, Co, Cu, Fe, Mn, and Zn was largely adequate during two to three months of TPN and that the human body may adapt to a somewhat low supply of zinc, 20-30 mumol/24 hr.

Selenium, glutathione-peroxidase and dermatitis herpetiformis.

The low levels of glutathione-peroxidase in blood from patients with dermatitis herpetiformis increased after 5 months selenium and vitamin E treatment. In this double-blind study no significant clinical improvement was, however, noted.

Elevated serum selenium in diabetic children.

Twenty-seven diabetic children, 16 girls and 11 boys, 5-18 years of age, with a duration of the disease ranging from 2-15 years, comprised the study group. Thirteen children with a similar age and sex distribution, living in the same area served as healthy controls. All 40 children had a normal growth pattern. The mean serum selenium concentration in the diabetic children, determined by neutron activation analysis, was 7.4 +/- 0.8 micrograms/100 ml (mean +/- SD) and in the healthy controls 6.5 +/- 0.8 micrograms/100 ml. The difference between the two groups was statistically highly significant (p less than 0.01). Boys and girls in both groups had nearly identical mean serum selenium levels and no correlation was observed between the selenium concentrations and either the age, weight or height of the children or the indicators of diabetic control. The selenium status in diabetic children has not been reported previously. The possibility of elevated serum selenium in diabetic children in response to altered lipid metabolism is discussed.

Analytical methods for trace elements in biological material.

Trace elements and essential trace elements are defined. The principal methods commonly used for their analysis in biological tissues are reviewed. The methods covered are chemical, electrochemical, optical spectrometry, X-ray spectrometry, mass spectrometry, and nuclear methods. The great importance of the sampling procedure and sample treatment is pointed out. The most sensitive, most generally applicable multi-element procedure is neutron activation analysis. The main drawbacks are that the procedure is time-consuming and expensive. Atomic absorption spectrometry is the most popular method. It is fast and inexpensive but can usually only be used as a single-element technique.

The concentrations of trace elements in blood from healthy newborn infants.

The concentrations of 14 elements in red cells and serum in 23 healthy newborn infants were determined with the aid of neutron activation analysis. Whole blood from seven mothers was also analysed. The mothers had no signs of trace element deficiency. In newborn infants the concentration of zinc in red cells was low and that of calcium was high, as compared with adults. The copper concentration in serum was low. In the newborn infants, higher ratios of intracellular to extracellular concentrations of sodium and potassium were found, as compared with adults. Iron and rubidium values in serum and red cells were similar to those found in adults. The ratio of intracellular to extracellular concentrations for chromium was two-the same value found in adults, although the levels were lower than reported in adults.

Trace elements in the human endometrium and decidua. A multielement analysis.

By means of neutron activation analysis, 25 trace elements, which are usually present in biological material, were estimated in 31 specimens of human endometrial tissue obtained at various phases of the menstrual cycle and in 14 specimens of decidua from the 12th to 18th week of pregnancy. Among the 13 trace elements invariably found in all specimens, the levels of copper, potassium, rubidium, antimony and zinc were significantly higher and those of bromine, selenium and sodium significantly lower in the endometrium than in the decidua. No difference was found in the levels of gold, calcium, cobalt, cesium and iron. Among the 12 trace elements which were found only occasionally, chromium, mercury, silver, and cadmium were detected in approximately half and cerium and scandium in approximately one-fourth of the 45 samples studied. Arsenic, barium, lanthanum, molybdenum, samarium and strontium were detected only rarely. The cyclic variations in the endometrial levels of calcium, rubidium and copper were highly significant and those in the levels of gold, cesium, iron, potassium and zinc probably significant.

Delayed elimination of the ototoxic compound atoxyl from the inner ear.

Whether an active accumulation of ototoxic substances or their metabolites occurs in the cochlea, or whether there exists a delayed elimination of these products from the endo-and perilymphatic fluids, following a passive equilibrium between the blood and the body tissues, is still a subject for discussion. To investigate the cochlear distribution of an ototoxic substance and its elimination rate, compared to other organs in the body, atoxyl, with known ototoxic effects (Anniko and Wersäll, 1975a, b; Anniko, 1976a, b) was used as a test substance. The neutron activation analysis technique was used to measure the atoxyl concentration in various parts of the body (cochlea, blood, muscle, kidney and cortical femoral bone) after various lengths of time following a subcutaneous injection of 100 mg/kg b.w. of atoxyl. Atoxyl was retained in the cochlea for a long period and a delayed elimination occurred from the inner ear. The excretion of atoxyl was likely to appear via the kidneys.

Albumin metabolism and gastrointestinal loss of protein in chronic renal failure.

The catabolism of albumin labelled with 125I has been studied in 10 patients with advanced renal failure and in 5 with nephrotic syndrome. In 10 patients the gastrointestinal protein loss was studied simultaneously by determing the faecal excretion during 7 days of 51Cr after i.v. administration of 51Cr-labelled chromic chloride. The results were related to a control group in which 12 subjects were studied with respect to albumin catabolism and 17 with respect to the gastrointestinal protein losses. The results showed that: 1) In the two patient groups the means for serum albumin concnetration and the intravascular albumin pool, expressed as g or g/kg b.wt., were significantly decreased compared with those of the control group. 2) The two patient groups had an increased extravascular albumin pool as well as an elevated ration between extra- and intravascular pools. 3) The mean albumin catabolic rate was not increased in the renal insufficiency group, expressed as a percentage of the intravascular pool/24 h or as g/24 h. In the patients with nephrotic syndrome, however, it was significantly increased. 4) The renal insufficiency group had a mean cumulative 51Cr excretion during 7 days of 1.6+/- 0.80% of the given dose, the control group 0.63+/- 0.30%. This difference is highly significant. The patients with nephrotic syndrome did not differ from the control group.

A perfluorochemical oxygen carrier (fluosol-43) in a synthetic medium used for perfusion of isolated rat liver.

An emulsion of perfluorotributylamine (Fluosol-43) was used as substitute for the gas-carrying function of erythrocytes in a synthetic medium for perfusion of isolated rat liver. The efficiency and effect of this synthetic gas-carrier were evaluated from measurements of the concentrations of rat albumin, the unsaturated vitamin B12-binding capacity of small-molecular-size vitamin B12-binding proteins (UBBC of SBP), urea nitrogen, glucose, sodium, potassium, alanine amino transferase (ALAT) in the medium, and the incorporation of 14C-lysine into the circulating proteins. Secretion of bile, portal pressure, PO2, PCO2 and pH in the affluent and the effluent mediums were also measured. The results demonstrate that the oxygen-carrying capacity of the medium and the metabolic functions of the liver were higher, and the liver damage less, when the medium included Fluosol-43 than without it. The albumin synthesis and the secretion of bile were as high as has been reported for perfusions with erythrocytes. This indicates that the oxygen carried by the Fluosol-43 was utilised by the liver, and that the metabolic functions were not adversely affected during 4 h of perfusion by the medium containing Fluosol-43.

A comparison of the content of iron in normal and rheumatoid striated muscle.

An investigation has been carried out on the presence of iron in striated muscle from normal individuals and from patients with rheumatoid disease. The methods used for the estimation of iron required a neutron activation analysis of total iron and extraction of hemoglobin in cyanide buffer. The results disclosed that there was a higher deposition of iron in rheumatoid muscle as compared with normals. Iron has a destructive effect on lysosomes and mast cells, the effect of which is an inflammatory reaction which may in part cause "metabolic myopathy" in rheumatoid disease. It is tentatively suggested that this "metabolic myopathy" may cause muscular pain and weakness in rheumatoid disease.

Studies on isolated rat liver perfused by perfluoro-compound emulsion.

Isolated rat livers were perfused for 6 hours by different types of cell-free synthetic media. Some of the media included perfluoro-compounds as an oxygen carrier. The value of the perfusion medium as blood substitute was judged on the basis of observations and measurements of a number of parameters. These were: secretion of bile, fluid pressure in the portal vein, the level of GPT (ALAT) transaminase, urea nitrogen, and glucose in the perfusate. The rate of albumin synthesis and the rate of 14-C-lysine incorporated into circulating proteins were also measured. It was found that perfusion of the isolated rat liver with the TC-199 Difco medium containing the perfluoro-compound FC-80 emulsion maintained the liver in a good condition demonstrated, among other things, by the synthesis of albumin and other proteins. The liver could be kept in a good functional condition during 6 hours perfusion with this cell-free medium. With all the other types of perfusate tested the liver did not synthesize proteins. The isolated rat liver seems to be both convenient and advantageous for testing the perfusion media with respect to their capacity to maintain important metabolic functions.